Increased expression of NAD(P)H oxidase in islets of animal models of Type 2 diabetes and its improvement by an AT1 receptor antagonist

Nakayama, Mizuho; Inoguchi, Toyoshi; Sonta, Toshiyo; Maeda, Yasutaka; Sasaki, Satoshi; Sawada, Fumi; Tsubouchi, Hirohito; Sonoda, Noriyuki; Kobayashi, Kazuo; Sumimoto, Hideki; Nawata, Hajime

doi:10.1016/j.bbrc.2005.05.065

Cited by 102 publications

(87 citation statements)

References 22 publications

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“…A BP-lowering effect as a result of PFD treatment cannot be ruled out in our studies; however, PFD was not found to lower BP in previous animal or human studies when BP was measured. 44 -46 Angiotensin receptor antagonists have been used in the db/db mouse model, [47][48][49][50][51][52][53] and generally show DN to be delayed by the use of ACEIs. 47 Although we have not performed comparative studies with blockers of renin-angiotensin system (RAS), we speculate that treatment with PFD will be additive to that of ACEIs and angiotensin antagonists.…”

Section: Discussionmentioning

confidence: 99%

Pirfenidone Is Renoprotective in Diabetic Kidney Disease

RamachandraRao

Zhu

Ravasi

et al. 2009

Journal of the American Society of Nephrology

152

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Although several interventions slow the progression of diabetic nephropathy, current therapies do not halt progression completely. Recent preclinical studies suggested that pirfenidone (PFD) prevents fibrosis in various diseases, but the mechanisms underlying its antifibrotic action are incompletely understood. Here, we evaluated the role of PFD in regulation of the extracellular matrix. In mouse mesangial cells, PFD decreased TGF-␤ promoter activity, reduced TGF-␤ protein secretion, and inhibited TGF-␤-induced Smad2-phosphorylation, 3TP-lux promoter activity, and generation of reactive oxygen species. To explore the therapeutic potential of PFD, we administered PFD to 17-wk-old db/db mice for 4 wk. PFD treatment significantly reduced mesangial matrix expansion and expression of renal matrix genes but did not affect albuminuria. Using liquid chromatography with subsequent electrospray ionization tandem mass spectrometry, we identified 21 proteins unique to PFD-treated diabetic kidneys. Analysis of gene ontology and protein-protein interactions of these proteins suggested that PFD may regulate RNA processing. Immunoblotting demonstrated that PFD promotes dosage-dependent dephosphorylation of eukaryotic initiation factor, potentially inhibiting translation of mRNA. In conclusion, PFD is renoprotective in diabetic kidney disease and may exert its antifibrotic effects, in part, via inhibiting RNA processing.

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Section: Discussionmentioning

confidence: 99%

Pirfenidone Is Renoprotective in Diabetic Kidney Disease

RamachandraRao

Zhu

Ravasi

et al. 2009

Journal of the American Society of Nephrology

152

View full text Add to dashboard Cite

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“…Importantly, the effects of an ACE inhibitor and an ARB on glucose tolerance in type 2 diabetic animals, including db/db mice, have been controversial, and depend on severity of diabetes, the time of start of drug treatment and the duration of drug treatment [25,26,41,42]. Furthermore, a recent clinical trial [43] showed that the addition of aliskiren to losartan, an ARB, provided additive reduction of urinary albumin excretion in type 2 diabetic patients, suggesting that the combination of aliskiren plus an ARB may be a useful therapeutic strategy for diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Aliskiren prevents cardiovascular complications and pancreatic injury in a mouse model of obesity and type 2 diabetes

et al. 2009

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Aims/hypothesis The effect of renin inhibition on type 2 diabetes is still unclear. The present study was undertaken to examine the efficacy of aliskiren, a direct renin inhibitor, on cardiovascular injuries, glucose intolerance and pancreatic injury in a mouse model of type 2 diabetes. Methods Groups of db/db mice, with obesity and type 2 diabetes, were treated with aliskiren (3, 6, 12 and 25 mg kg −1 day −1 ) or hydralazine (80 mg kg −1 day −1 ) for 6 weeks, and the protective effects were extensively compared among groups.Results All sub-pressor and hypotensive doses of aliskiren significantly attenuated cardiac fibrosis, macrophage infiltration and coronary remodelling, and improved vascular endothelial function in db/db mice. These protective effects of aliskiren were attributed to the attenuation of cardiac p22 phox -related NADPH oxidase-induced superoxide and the restoration of vascular endothelial nitric oxide synthase (eNOS) production. Aliskiren at the highest dose (25 mg kg), but not at lower doses, partially reduced glucose intolerance in db/db mice. Furthermore, the highest dose of aliskiren significantly attenuated the decreases in pancreatic islet insulin content and beta cell mass, and prevented pancreatic islet fibrosis in db/db mice, being associated with the reduction of 8-hydroxy-2′-deoxyguanosine-positive cells and Nox2 (also known as Cybb) expression in pancreatic islets by aliskiren. Conclusions/interpretation Our work provides the first evidence that direct renin inhibition with aliskiren protects against cardiovascular complications and pancreatic injury, through the attenuation of oxidative stress. Thus, we propose that aliskiren may be a promising therapeutic agent for type 2 diabetes.

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“…In an animal model of type II diabetes, increased expression of Nox1 was found in the islets [29]. However, Nox1, 2 and 4 were detected in pancreatic islet cells and a Nox inhibitor suppressed the glucose-stimulated insulin secretion.…”

Section: Insulin Action and Secretionmentioning

confidence: 98%